An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

Bangma, Jacqueline T.; Szilagyi, John T.; Blake, Bevin E.; Plazas, Cinthya; Kepper, Stewart L; Fenton, Suzanne E.; Fry, Rebecca C.

doi:10.1002/tox.23004

Cited by 42 publications

(22 citation statements)

References 57 publications

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“…These concentration ranges overlap with concentrations of PFAS reported in serum of people in highly contaminated communities (PFOA: 17.6 μg/ml; Steenland et al, 2009 ). PFAS concentrations reported in the serum of pregnant women (PFOS in the 95th percentile of exposure = 0.018 μg/ml; Bommarito et al, 2021 ) and concentrations measured in human placental samples (maximum PFHxA = 0.006 μg/g; Bangma et al, 2020b ) are within two to four orders of magnitude of the concentrations tested in the present work. Notably, Bommarito et al (2021) reported maternal PFOS exposure was associated with higher odds of late-onset preeclampsia (OR = 1.60, 95% CI: 1.06, 2.43).…”

Section: Discussionsupporting

confidence: 62%

A High-Throughput Toxicity Screen of 42 Per- and Polyfluoroalkyl Substances (PFAS) and Functional Assessment of Migration and Gene Expression in Human Placental Trophoblast Cells

2022

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Per- and polyfluoroalkyl substances (PFAS) have become ubiquitous environmental contaminants that have been associated with adverse pregnancy outcomes in women and experimental research models. Adverse developmental and reproductive outcomes have been investigated for relatively few PFAS, and such studies are not scalable to address the thousands of unique chemical structures. As the placenta has been reported as a PFAS target tissue, the human placental trophoblast JEG-3 cell line was employed in a high-throughput toxicity screen (HTTS) to evaluate the effects of 42 unique PFAS on viability, proliferation, and mitochondrial membrane potential (MMP). HTTS concentration-response curve fitting determined EC50 values for 79% of tested compounds for at least one of the three endpoints. Trophoblast migratory potential was evaluated for a subset of six prioritized PFAS using a scratch wound assay. Migration, measured as the percent of wound closure after 72 h, was most severely inhibited by exposure to 100 µM perfluorooctanoic acid (PFOA; 72% closure), perfluorooctanesulfonic acid (PFOS; 57% closure), or ammonium perfluoro-2-methyl-3-oxahexanoate (GenX; 79% closure). PFOA and GenX were subsequently evaluated for disrupted expression of 46 genes reported to be vital to trophoblast health. Disrupted regulation of oxidative stress was suggested by altered expression of GPEX1 (300 µM GenX and 3 µM GenX), GPER1 (300 µM GenX), and SOD1 and altered cellular response to xenobiotic stress was indicated by upregulation of the placental efflux transporter, ABCG2 (300 µM GenX, 3 µM GenX, and 100 µM PFOA). These findings suggest the placenta is potentially a direct target of PFAS exposure and indicate that trophoblast cell gene expression and function are disrupted at PFAS levels well below the calculated cytotoxicity threshold (EC50). Future work is needed to determine the mechanism(s) of action of PFAS towards placental trophoblasts.

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Section: Discussionsupporting

confidence: 62%

A High-Throughput Toxicity Screen of 42 Per- and Polyfluoroalkyl Substances (PFAS) and Functional Assessment of Migration and Gene Expression in Human Placental Trophoblast Cells

2022

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“…Numerous studies have illustrated that exposure to PFOA adversely affects the different organ tissues or cells, such as inducing splenic atrophy, 9 promoting diabetic renal injury, 10 affecting immune organs function, 11 inducing developmental cardiotoxicity, 12 and regulating inflammatory response 13 14 impairing sperm motility, 15 disrupting the hormonal pathways, 16 and causing placental abnormalities, 4,17 as well as its adverse effects on offspring growth and development 18–21 . Moreover, a study of IVF data in humans showed that the maternal plasma PFOA concentration was inversely correlated with the number of obtained oocytes, mature oocytes, 2PN fertilized oocytes, and high‐quality embryos, suggesting that PFOA hurts the female reproductive system 22 .…”

Section: Introductionmentioning

confidence: 99%

Perfluorooctanoic acid exposure in vivo perturbs mitochondrial metabolic during oocyte maturation

Zhang

et al. 2022

Environmental Toxicology

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Perfluorooctanoic acid (PFOA), a member of a group of polyfluorinated and perfluorinated alkyl substances (PFAS), is associated with adverse pregnancy outcomes in mammals. However, the effects of in vivo exposure to PFOA on the female reproductive system and the underlying mechanisms remain unclear. In our study, we constructed a mouse model to investigate whether low-dose PFOA (1 mg/kg/day) or high-dose PFOA (5 mg/kg/day) affect meiosis maturation of oocytes and the potential mechanisms that may be associated with oocyte maturation disorder. Our results indicate that low-dose and high-dose PFOA can lead to impaired oocyte maturation, which is manifested by decreased rate of embryonic foam rupture and first polar body extrusion. Moreover, PFOA exposure harmed the mitochondrial metabolic, resulting in low levels of ATP contents, high reactive oxygen species, aberrant mitochondrial membrane potential. In addition, the proportion of DNA damage marker γ-H2AX was also significantly increased in PFOA exposure oocytes. These changes lead to abnormal arrangements of the spindle and chromosomes during oocyte maturation. In conclusion, our results for the first time illustrated that exposure to PFOA in vivo in female mice impaired the meiosis maturation of oocytes, which provided a basis for studying the mechanism of PFOA reproductive toxicity in female mammals.

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“…Thus, studying the effects of short‐chain PFAS on placental cells is of considerable significance while studying human health effects. A study using HT cells (another placental trophoblast model) found that serum‐free media (SFM) contained no detectable PFAS; however, fetal bovine serum‐supplemented media (SSM) was contaminated with legacy PFAS that have the potential to alter the outcomes experiments carried out using fetal bovine serum (Bangma et al, 2020). Albeit the PFAS from the supplemented media were not found in the JEG‐3 cells in this study, however, it highlights another consideration when selecting the culture conditions for short‐chain PFAS studies.…”

Section: Advantages and Limitations Of In Vitro Methodsmentioning

confidence: 99%

The use of in vitro methods in assessing human health risks associated with short‐chain perfluoroalkyl and polyfluoroalkyl substances (PFAS)

Solan

Lavado

2021

J of Applied Toxicology

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Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a large class of industrial chemicals with a ubiquitous and persistent presence in the environment. Of the thousands of PFAS used by consumers and industry, very few have been thoroughly characterized for potential adverse effects. This is especially true for the novel shortchain (C < 8) alternatives that replaced legacy PFAS. Perfluoroalkyl and polyfluoroalkyl substances have revealed inconsistencies in the toxicokinetics predicted by animal models and empirical findings in humans. To adequately assess the possible health effects of short-chain PFAS, there is a need for robust aggregated data sets on the mechanistic underpinnings and physiochemical properties of these alternatives.Acquiring relevant data on the health effects of short-chain PFAS can be achieved through high-throughput methods supported by in vitro human cell-based models. This review briefly summarizes some of the toxicity data obtained using human cells in vitro, discusses the advantages and limitations of cell-based models, and provides insights on potential solutions to challenges presented with the use of these methods for use in safety assessments.

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An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

Cited by 42 publications

References 57 publications

A High-Throughput Toxicity Screen of 42 Per- and Polyfluoroalkyl Substances (PFAS) and Functional Assessment of Migration and Gene Expression in Human Placental Trophoblast Cells

A High-Throughput Toxicity Screen of 42 Per- and Polyfluoroalkyl Substances (PFAS) and Functional Assessment of Migration and Gene Expression in Human Placental Trophoblast Cells

Perfluorooctanoic acid exposure in vivo perturbs mitochondrial metabolic during oocyte maturation

The use of in vitro methods in assessing human health risks associated with short‐chain perfluoroalkyl and polyfluoroalkyl substances (PFAS)

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